Method for the elimination of nematode infestations



United States Patent York No Drawing. Filed Apr. 24, 1961, Ser. No. 104,798 6 (Ilaims. (Ql. 167-53) The present invention relates to the discovery that the following novel group of di-stilbazoles, expressed in Formula I, have marked activity against nematode infestations of the intestinal tract In the above formula R is selected from the class consisting of methyl, ethyl, n-propyl, n-butyl and benzyl radicals, R is selected from the class consisting of the methyl and ethyl radicals, and NR may also be pyrrolidino or piperidino and X-* is the anion of a non-toxic pharmaceutically acceptable acid.

The parasites of particular concern are pin-worms (Enterobius vermicularis, Syphacia obvelata and Aspicul'uris tetraptera of mice) and hook-worms (Ancylostoma duodenale and Necator americanus and Ancylostoma caninum of dogs). The pin-worms of mice are primarily of interest as test-organisms, Syphacia especially having been found to be a reliable indicator of the elfectiveness of drugs against human pin-worm. The hook-worms of dogs are both test-organisms and parasites of some importance in their own right since severe infestations by canine hook-worm are common among dogs in the South of the United States, and light infestations are fairly frequent in the North.

Some of the compounds of Formula I have been described previously but none have ever been examined as anthelmintics. The doses required vary somewhat with the parasite and with the host, and rather less with the individual compounds. Against mouse pin-worms oral doses of 5-20 mg./kg. eliminate all or virtually all the worms in one treatment. With dogs hook-worms are well eliminated by compound V (Table I) in a single dose of 25 trig/kg. The whip-worm, Trz'curis vulpis, requires the same sized dose but repeated twice a day for three days. The common round-worm of dogs (Toxocara canz's) is also vulnerable to this compound.

These compounds are conveniently prepared by condensation or" two equivalents of an aldehyde:

with a quarternary salt of 2,6-lutidine The condensation is conveniently run in a lower alcohol with a secondary amine, such as piperidine, as catalyst. When X- in the above formula is iodide ion (correspond- 3,085,935, Patented Apr. 16, 1963 ing to an .alkiodide of lutidine) the condensation product, I, is relatively insoluble and precipitates in the course of the reaction. The yields of I, so obtained, are nearly quantitative.

Of the p-dialkylaminobenzaldehydes required for this synthesis, padimethylamino and p-diethylaminobenzaldehydes are known. The preparation of p-pyrrolidino and p-piperidinobenzaldehydes is described in a companion application. The nature of R, beyond being a lower alkyl.

group, is pretty well determined by the chemistry of the situation. The normal diminution in the reactivity of alkyl halides with the increasing size of the alkyl group is here accentuated by the hindrance of the 2,6-lutidine.

As a result R cannot be a branched group and its size is pretty well limited at four carbons. The more reactive benzyl is, however, usable.

In the doses employed iodide ion is sufliciently nontoxic. Bromide or chloride or methyl sulfate and ptoluene sulfonate are other convenient values for X cates the critical character of the structure-activity relationships. All of these results were obtained with single doses administered orally. It will be observed (cf. cpds. I-V) that substitution by a [dialkylamino group in the benzenoid rings is essential for high activity and that this substitution must be in the para position (compare III and V). Auxiliary substitution is undesirable (compare IV and V). Taking p-dialkylamino substitution as essential it will be seen that high activity ceases above diethylamino (VIII-X) but that pyrollidino and piperidino are satisfactory values for NR Morpholino and N'-alkyl piperazino substitutions give relatively inactive compounds (XVI-XVII).

Provided NR has an acceptable value, R may vary considerably. It will be seen from the table that all variations of R Within the definition give active compounds. Of these, however, the methiodides and ethiodides are very much the most accessible.

PREPARATION OF THE DI-STILBAZOLES All of the di-stilbazoles were prepared by essentially thesame method. Compounds V and VI of Table I were reported by Crippa and Verdi (Ann. chim. applioata, 26, 418 (1936) (Chem. Abs. 31, 2214" (1937).

2,-6-bz's (p-pyrrolidinostyryl) pyridine ethiodide (compound XII of the table).A mixture containing 2.6 g. of 2,6-lutidine ethiodide, 100 cc. of methanol, 4.2 g. of p-pyrrolidinobenzaldehyde and 1 cc. of piperidine was refluxed on a steam bath. Insoluble solid precipitated and heavy bumping started in less than one hour. After 2 hours this product was collected (2 g.) and the filtrates were refluxed for 20 hours longer. A second crop of 2.5 g. was obtained and on standing another day or so the filtrates gave a third crop of one g. The total yield was 5.5 g. (-85%) in three crops, M.P. 282-283 C. The product was nearly insoluble in hot methanol and was purified by washing several times With ether and then digesting one or two times with 10-20 times its weight of hot methanol. Because it is difficult to recrystallize it is desirable that nearly all insoluble impurities (dust, boiling stones, etc.) be removed from the easily purified reactants before the final condensation step and be kept out as much as possible thereafter.

Table I Substitution in benzene rings Percent worms removed Dose. nag/Kg.

4-CH3O 2-N(CH3) z--CH3 VII-..

VIII

XVII.

4-N(CH CH2CH:)2

4-N(CH:C5H5)2 C H5CH2 11-C4Hn M \I HM HHN} r-u- N: i-nm HM t- Nn- M HMP-M' l-u- 00 010010 0010 momo 01cc ooooovoooouvmcuocovcncuv oncom amazes 10:08 soccer: in! umzocow woocomscnzozo sm M coo ours wooco oo cnqacr ONO: vm wficcoworocawqoww-q owitmmuomw These substances can be presented in capsules or as compressed tablets or can be administered in a chewing wafer.

What we claim is: 1. A method of eradicating infestations of parasitic nematodes inhabiting the intestinal tract which comprises administering orally to the host of the infested locus a compound represented by the formula nematodes inhabiting the intestinal tract which comprises administering orally to the host of the infested locus 2,6- bis (p-dimcthylaminostyryl) pyridine methiodide.

3. A method of eradicating infestations of parasitic nematodes inhabiting the intestinal tract which comprises administering orally to the host of the infested locus 2,6 bis (p-diethylaminostyryl) methiodide.

4. A method of eradicating infestations of parasitic nematodes inhabiting the intestinal tract which comprises administering orally to the host of the infested locus 2,6-bis (p-dimethylaminostyryl) pyridine ethiodide.

5. A method of eradicating infestations of parasitic nematodes inhabiting the intestinal tract which comprises administering orally to the host of the infested locus 2,6-bis (p-dimethylaminostyryl)pyridine benzyl iodide.

6. A method of eradicating infestations of parasitic nematodes inhabiting the intestinal tract which comprises administering orally to the host of the infested locus 2,6-bis (p-pyrrolidinostyryl) pyridine ethiodide.

No references cited. 

1. A METHOD OF ERADICATING INFESTATIONS OF PARASITIC NEMATODES INHABITING THE INTESTINAL TRACT WHICH COMPRISES ADMINISTERING ORALLY TO THE HOST OF THE INFESTED LOCUS A COMPOUND REPRESENTED BY FORMULA 